Brain Levels Research Articles

Neuroprotective and cognitive enhancing effects of herbecetin against thioacetamide induced hepatic encephalopathy in rats via upregulation of AMPK and SIRT1 signaling pathways

Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological characteristics. The purpose of this study was to assess the ability of herbacetin to protect against the cognitive deficits associated with thioacetamide (TAA) rat model and delineate the underlying behavioral and pharmacological mechanisms. Rats were pretreated with herbacetin (20 and 40 mg/kg) for 30days. On 30th day, the rats were injected with TAA (i.p. 350 mg/kg) in a single dose. In addition to a histpathological studies, ultra-structural architecture of the brain, liver functions, oxidative stress biomarkers, and behavioral tests were evaluated. Compared to the TAA-intoxicated group, herbacetin improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels. Herbacetin reduced brain levels of malodialdeyde, glutamine synthetase (GS), tumor necrosis factor- alpha (TNF-α), interleukin 1 B (IL-1β), annexin v, and increased brain GSH, Sirtuin 1 (SIRT1), and AMP-activated kinase (AMPK) expression levels. Also, herbacetin improve the histopathological changes and ultra- structure of brain tissue via attenuating the number of inflammatory and apoptotic cells. Herbacetin treatment significantly reduced the toxicity caused by TAA. These findings suggest that herbacetin might be taken into account as a possible neuroprotective and cognitive enhancing agent due to its ability to reduce oxidative stress, inflammation and apoptosis associated with TAA.

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson’s Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets.

Quercetin Inhibits Neuronal Pyroptosis and Ferroptosis by Modulating Microglial M1/M2 Polarization in Atherosclerosis.

Atherosclerosis (AS) with iron and lipid overload and systemic inflammation is a risk factor for Alzheimer's disease. M1 macrophage/microglia participate in neuronal pyroptosis and recently have been reported to be the ferroptosis-resistant phenotype. Quercetin plays a prominent role in preventing and treating neuroinflammation, but the protective mechanism against neurodegeneration caused by iron deposition is poorly understood. ApoE-/- mice were fed a high-fat diet with or without quercetin treatment. The Morris water maze and novel object recognition tests were conducted to assess spatial learning and memory, and nonspatial recognition memory, respectively. Prussian blue and immunofluorescence staining were performed to assess the iron levels in the whole brain and in microglia, microglia polarization, and the degree of microglia/neuron ferroptosis. In vitro, we further explored the molecular biological alterations associated with microglial polarization, neuronal pyroptosis, and ferroptosis via Western blot, flow cytometry, CCK8, LDH, propidium iodide, and coculture system. We found that quercetin improved brain lesions and spatial learning and memory in AS mice. Iron deposition in the whole brain or microglia was reversed by the quercetin treatment. In the AS group, the colocalization of iNOS with Iba1 was increased, which was reversed by quercetin. However, the colocalization of iNOS with PTGS2/TfR was not increased in the AS group, suggesting a character resisting ferroptosis. Quercetin induced the expression of Arg-1 and decreased the colocalizations of Arg-1 with PTGS2/TfR. In vitro, ox-LDL combined with ferric ammonium citrate treatment (OF) significantly shifted the microglial M1/M2 phenotype balance and increased the levels of free iron, ROS, and lipid peroxides, which was reversed by quercetin. M1 phenotype induced by OF caused neuronal pyroptosis and was promoted to ferroptosis by L-NIL treatment, which contributed to neuronal ferroptosis as well. However, quercetin induced the M1 to M2 phenotype and inhibited M2 macrophages/microglia and neuron pyroptosis or ferroptosis. In summary, quercetin alleviated neuroinflammation by inducing the M1 to M2 phenotype to inhibit neuronal pyroptosis and protected neurons from ferroptosis, which may provide a new idea for neuroinflammation prevention and treatment.

S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway.

The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aβ)-40, Aβ42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aβ levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

Pineapple (Ananas comosus) Ameliorates Depressant-like Behaviors in Rats Induced by Lipopolysaccharide

Abstract Background: Lipopolysaccharide (LPS) injection can lead to depression and mood disorders by reducing tryptophan availability through increased activity of the enzyme indoleamine 2,3-dioxygenase. Tryptophan, sourced from fruits such as pineapple (Ananas cosmosus), is vital for the body, especially the serotonergic system. Aim: This study aims to assess how pineapple pulp (PP) counters LPS-induced depressive behaviors in male Wistar rats. Methods: The experiment involved force-feeding PP for 28 days before LPS injection (0.5 mg/kg intraperitoneal [i.p.]) in 30 male Wistar rats, divided into five groups. Groups I (normal) and II (LPS control) received 15 ml aquadest/kg/day. Test Groups III, IV, and V were given varied doses of PP; low dose (3.75 ml/kg/day), medium dose (7.5 ml/kg/day), and high dose (15 ml/kg/day). At the study's end, rats underwent the open field test (OFT) and the tail suspension test (TST). In addition, blood and brain samples were analyzed for neuroendocrine markers related to depression. Results: LPS triggers depressive symptoms, as evidenced by increased immobility time in the TST and altered behaviors indicative of anxiety in the OFT, especially in groups not receiving PP. This is followed by decreased serotonin levels in both plasma and brain when compared to groups given PP. In addition, higher corticosterone levels were observed in the LPS group than in the PP-treated group. Administering PP at 7.5 ml/kg/day for 28 days can alleviate the depressive effects induced by LPS injection. Conclusion: PP may have antidepressant properties, potentially by mitigating behaviors leading to depressive symptoms.

Objectivization study of acupuncture Deqi and brain modulation mechanisms: a review.

Deqi is an important prerequisite for acupuncture to achieve optimal efficacy. Chinese medicine has long been concerned with the relationship between Deqi and the clinical efficacy of acupuncture. However, the underlying mechanisms of Deqi are complex and there is a lack of systematic summaries of objective quantitative studies of Deqi. Acupuncture Deqi can achieve the purpose of treating diseases by regulating the interaction of local and neighboring acupoints, brain centers, and target organs. At local and neighboring acupoints, Deqi can change their tissue structure, temperature, blood perfusion, energy metabolism, and electrophysiological indicators. At the central brain level, Deqi can activate the brain regions of the thalamus, parahippocampal gyrus, postcentral gyrus, insular, middle temporal gyrus, cingulate gyrus, etc. It also has extensive effects on the limbic-paralimbic-neocortical-network and default mode network. The brain mechanisms of Deqi vary depending on the acupuncture techniques and points chosen. In addition, Deqi 's mechanism of action involves correcting abnormalities in target organs. The mechanisms of acupuncture Deqi are multi-targeted and multi-layered. The biological mechanisms of Deqi are closely related to brain centers. This study will help to explore the mechanism of Deqi from a local-central-target-organ perspective and provide information for future clinical decision-making.

Intraperitoneally injected d11-11(12)-epoxyeicosatrienoic acid is rapidly incorporated and esterified within rat plasma and peripheral tissues but not the brain

Epoxyeicosatrienoic acids (EpETrEs) are bioactive lipid mediators of arachidonic acid cytochrome P450 oxidation. In vivo, the free (unbound) form of EpETrEs regulate multiple processes, including blood flow, angiogenesis and inflammation resolution. Free EpETrEs are thought to rapidly degrade via soluble epoxide hydrolase (sEH), yet, in many tissues the majority of EpETrEs are esterified to complex lipids (e.g. phospholipids) suggesting that esterification may play a more dominant role in regulating free, bioactive EpETrE levels. This hypothesis was tested by quantifying the metabolism of intraperitoneally injected free d11-11(12)-Epoxyeicosatrienoic acid (d11-11(12)-EpETrE) in male and female rats. Plasma and tissues (liver, adipose and brain) were obtained 3 to 4 minutes later and assayed for d11-11(12)-EpETrE and its sEH metabolite, d11-11,12-dihydroxyeicosatrienoic acid (d11-11,12-diHETrE) in both the free and esterified lipid fractions. In both males and females, the majority of injected tracer was recovered in liver followed by plasma and adipose. No tracer was detected in the brain, indicating that brain levels are maintained by endogenous synthesis from precursor fatty acids. In plasma, liver, and adipose, the majority (>54%) of d11-11(12)-EpETrE was found esterified to phospholipids and neutral lipids (triglycerides and cholesteryl esters). sEH-derived d11-11,12-diHETrE was not detected in plasma or tissues, suggesting negligible conversion within the 3-4 min period post tracer injection. This study shows that esterification is the main pathway regulating free 11(12)-EpETrE levels in vivo.

Sex-dependent effects of monomeric α-synuclein on calcium and cell death of lateral hypothalamic mouse neurons are altered by orexin

Parkinson's Disease (PD) patients experience sleeping disorders in addition to the disease-defining symptomology of movement dysfunctions. The prevalence of PD is sex-based and presence of sleeping disorders in PD also shows sex bias with a stronger phenotype in males. In addition to loss of dopamine-containing neurons in the striatum, arousal-related, orexin-containing neurons in the lateral hypothalamus (LH) are lost in PD, which could contribute to state-related disorders. As orexin has been shown to be involved in sleeping disorders and to have neuroprotective effects, we asked whether orexin could protect sleep-related LH neurons from damage putatively from the protein α-synuclein (α-syn), which is found at high levels in the PD brain and that we have shown is associated with putatively excitotoxic rises in intracellular calcium in brainstem sleep-controlling nuclei, especially in males. Accordingly, we monitored intracellular calcium transients induced by α-syn and whether concurrent exposure to orexin affected those transients in LH cells of the mouse brain slice using calcium imaging. Further, we used an assay of cell death to determine whether LH cell viability was influenced when α-syn and orexin were co-applied when compared to exposure to α-syn alone. We found that excitatory calcium events induced by α-syn were reduced in amplitude and frequency when orexin was co-applied, and when data were evaluated by sex, this effect was found to be greater in females. In addition, α-syn exposure was associated with cell death that was higher in males, and interestingly, reduced cell death was noted when orexin was present, which did not show a sex bias. We interpret our findings to indicate that orexin is protective to α-syn-mediated damage to hypothalamic neurons, and the actions of orexin on α-syn-induced cellular effects differ between sexes, which could underlie sex-based differences in sleeping disorders in PD.

A comprehensive assessment of the cholinergic-supporting and cognitive-enhancing effects of Rosa damascena Mill. (Damask rose) essential oil on scopolamine-induced amnestic rats.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual loss of cognitive abilities (dementia) and is a major public health problem. Here, we aimed at investigating the effects of Rosa damascena essential oil (RDEO) on learning and memory functions in a rat model of amnesia induced by scopolamine, as well as on changes in acetylcholinesterase (AChE) activity, M1 muscarinic acetylcholine receptor (mAChR) expression, and brain-derived neurotrophic factor (BDNF) levels in the extracted brain tissues. The control, amnesia (scopolamine, 1mg/kg/i.p.) and treatment (RDEO, 100μL/kg/p.o. or galantamine, 1.5mg/kg/i.p.) groups were subjected to Morris water maze and new object recognition tests. AChE activity was assayed by ELISA, and M1 mAChR and BDNF concentration changes were determined by western blotting. Also, using computational tools, human M1 mAChR was modeled in an active conformation, and the major components of RDEO were docked onto this receptor. According to our behavioral tests, RDEO was able to mitigate the learning and memory impairments caused by scopolamine in vivo. Our in vitro assays showed that the observed positive effects correlated well with a decrease in AChE activity and an increase in M1 mAChR and BDNF levels in amnestic rat brains. We also demonstrated in an in silico setting that the major components of RDEO, specifically -citronellol, geraniol, and nerol, could be accommodated favorably within the allosteric binding pocket of active-state human M1 mAChR and anchored here chiefly by hydrogen-bonding and alkyl-π interactions. Our findings offer a solid experimental foundation for future RDEO-based medicinal product development for patients suffering from AD.

Lifestyle Modulators of Neuroplasticity in Parkinson's Disease: Evidence in Human Neuroimaging Studies.

Parkinson's disease (PD) is a neurodegenerative disease characterized by both motor and non-motor symptoms. A progressive neuronal loss and the consequent clinical impairment lead to deleterious effects on daily living and quality of life. Despite effective symptomatic therapeutic approaches, no disease-modifying therapies are currently available. Emerging evidence suggests that adopting a healthy lifestyle can improve the quality of life of PD patients. In addition, modulating lifestyle factors can positively affect the microstructural and macrostructural brain levels, corresponding to clinical improvement. Neuroimaging studies may help to identify the mechanisms through which physical exercise, dietary changes, cognitive enrichment, and exposure to substances modulate neuroprotection. All these factors have been associated with a modified risk of developing PD, with attenuation or exacerbation of motor and non-motor symptomatology, and possibly with structural and molecular changes. In the present work, we review the current knowledge on how lifestyle factors influence PD development and progression and the neuroimaging evidence for the brain structural, functional, and molecular changes induced by the adoption of positive or negative lifestyle behaviours.

Hyperhomocysteinemia Transcriptionally Regulates Expression of a Set of Ion Channels in Brain and Heart Tissues in Mice

The alterations of ion channel gene expressions in brain and heart tissues in HHcy have not been previously reported. We investigated the mRNA expression levels in brain and heart tissues of the HHcy mice compared to the control mice to characterize distinct expression of 36 ion channels. C57BL/6 J. mice were divided into two groups of 15 animals each: (1) control group and (2) HHcy group. The HHcy was induced by methionine administiration. The mRNA levels of ion channels were analyzed using qRT-PCR. TUNEL staining and MDA assay were used for verification of the negative side effects of HHcy in heart and brain tissues. RT-PCR revealed the upregulation of Hcn4, Trpc3, Trpm2 and the downregulation of Abbc8, Cacna1b, Cacna1c, Cacna1e, Cacna1h, Hcn1, Kcnc3, Kcnh7, Kcnj8, Trpc4, Trpc5, Trpc6, Trpm3, Trpm4, Trpv4, Trpv6 in brain tissues of the HHcy group compared to the control. The upregulation of ion channel expressions in heart tissues were not detected, but we found only the downregulation of Accn1, Accn2, Accn3, Hcn1, Kcnc4 and Trpv6 ion channels. Apoptozis and MDA level were significantly increased in brain and heart tissues of the HHcy group compared to the control. Brain tissues compared to heart tissues exhibit a very considerable and diverse ion channel gene expression pattern in mice with HHcy than control. Clarifying the roles of ion channels in HHcy could shed light on the development of novel therapeutic strategies and ultimately improve HHcy side effects.

Epidemiology of Disorders of the Gut-Brain Interaction: An Appraisal of the Rome IV Criteria and Beyond.

Disorders of the gut-brain interaction (DGBIs) are presently classified into mutually exclusive anatomical area-related symptom-based categories according to the Rome IV criteria. The pathophysiology of visceral nociception, which contributes to the wide range of symptoms of DGBIs, involves complex psychobiological processes arising from the bidirectional interactions of multiple systems at the gut and brain levels, which affect symptom expression and illness behaviors. The attitude toward an illness and expression of pain and bowel habit vary across cultures with variable interpretation based on sociocultural beliefs, which may not tally with the medical definitions. Thus, psychological factors impact DGBI definitions, their severity and health care utilization. Due to the poor localization and multisegment referral of visceral pain, the anatomical site of pain may not correspond to the affected segment, and there may be a variable degree of overlap among symptoms. The somewhat restrictively defined Rome IV criteria assume one-to-one correlation of symptoms with underlying pathophysiology and ignore overlapping DGBIs, nonstandardized symptom categories, and change or shift in category over time. The microorganic nature of DGBIs resulting from systemic, metabolic or motility disorders, gut dysbiosis and inflammation are not addressed in the Rome IV criteria. Although there is a multidimensional clinical profile that does address these factors, it is not followed rigorously in practice. Threshold changes for diagnostic criteria or addition/deletion of symptoms leads to wide variation among different DGBI criteria resulting in uncertain comparability of results. Although the Rome IV criteria are excellent for research studies and therapeutic trials in homogenous populations, further improvement is needed for their wider applicability in clinical practice.

Hooded crows (Corvus cornix) manufacture objects relative to a mental template

It was recently found that not only tool-specialized New Caledonian crows, but also Goffin cockatoos can manufacture physical objects in accordance with a mental template. That is, they can emulate features of existing objects when they manufacture new items. Both species spontaneously ripped pieces of card into large strips if they had previously learned that a large template was rewarded, and small strips when they previously learned that a small template was rewarded. Among New Caledonian crows, this cognitive ability was suggested as a potential mechanism underlying the transmission of natural tool designs. Here, we tested for the same ability in another non-specialised tool user–Hooded crows (Corvus cornix). Crows were exposed to pre-made template objects, varying first in colour and then in size, and were rewarded only if they chose pre-made objects that matched the template. In subsequent tests, birds were given the opportunity to manufacture versions of these objects. All three crows ripped paper pieces from the same colour material as the rewarded template, and, crucially, also manufactured objects that were more similar in size to previously rewarded, than unrewarded, templates, despite the birds being rewarded at random in both tests. Therefore, we found the ability to manufacture physical objects relative to a mental template in yet another bird species not specialized in using or making foraging tools in the wild, but with a high level of brain and cognitive development.

Bacillus Calmette-Guérin (BCG)-Induced Protection in Brain Disorders.

The Bacille Calmette-Guerin (BCG) vaccine is one of the most widely used vaccines in the world for the prevention of tuberculosis. Its immunological capacity also includes epigenetic reprogramming, activation of T cells and inflammatory responses. Although the main usage of the vaccine is the prevention of tuberculosis, different works have shown that the effect of BCG can go beyond the peripheral immune response and be linked to the central nervous system by modulating the immune system at the level of the brain. This review therefore aims to describe the BCG vaccine, its origin, its relationship with the immune system, and its involvement at the brain level.

Synthesis and evaluation of a 68Ga-labeled spermine derivative for tumor PET imaging

BackgroundThe polyamine transporter system (PTS), which renders it a promising target for tumor therapy and imaging applications, facilitates the transmembrane transport of polyamines. We reported a novel derivative of spermine labeled with gallium-68 ([68Ga]Ga-NOTA-Spermine) for the imaging of the PTS in mouse models of tumor. ResultsThe radiochemical yield of [68Ga]Ga-NOTA-Spermine was determined to be 64–69 %, demonstrating exceptional stability and radiochemical purity (>98 %). Cellular uptake experiments revealed that A549 cells exhibited peak uptake of [68Ga]Ga-NOTA-Spermine at 90 min (15.4 % ± 0.68 %). Biodistribution analysis demonstrated significant accumulation of [68Ga]Ga-NOTA-Spermine in kidneys and liver, while exhibiting low uptake levels in muscle, brain, and bones. Furthermore, Micro-PET/CT scans conducted on A549 tumor-bearing mouse models indicated substantial uptake of [68Ga]Ga-NOTA-Spermine, with maximum tumor/muscle (T/M) ratios reaching 3.71. ConclusionThese results suggest that [68Ga]Ga-NOTA-Spermine holds potential as a PET imaging agent for tumors with high levels of PTS.

Changes in high-order interaction measures of synergy and redundancy during non-ordinary states of consciousness induced by meditation, hypnosis, and auto-induced cognitive trance

High-order interactions are required across brain regions to accomplish specific cognitive functions. These functional interdependencies are reflected by synergistic information that can be obtained by combining the information from all the sources considered and redundant information (i.e., common information provided by all the sources). However, electroencephalogram (EEG) functional connectivity is limited to pairwise interactions thereby precluding the estimation of high-order interactions. In this multicentric study, we used measures of synergistic and redundant information to study in parallel the high-order interactions between five EEG electrodes during three non-ordinary states of consciousness (NSCs): Rajyoga meditation (RM), hypnosis, and auto-induced cognitive trance (AICT). We analyzed EEG data from 22 long-term Rajyoga meditators, nine volunteers undergoing hypnosis, and 21 practitioners of AICT. We here report the within-group changes in synergy and redundancy for each NSC in comparison with their respective baseline. During RM, synergy increased at the whole brain level in the delta and theta bands. Redundancy decreased in frontal, right central, and posterior electrodes in delta, and frontal, central, and posterior electrodes in beta1 and beta2 bands. During hypnosis, synergy decreased in mid-frontal, temporal, and mid-centro-parietal electrodes in the delta band. The decrease was also observed in the beta2 band in the left frontal and right parietal electrodes. During AICT, synergy decreased in delta and theta bands in left-frontal, right-frontocentral, and posterior electrodes. The decrease was also observed at the whole brain level in the alpha band. However, redundancy changes during hypnosis and AICT were not significant. The subjective reports of absorption and dissociation during hypnosis and AICT, as well as the mystical experience questionnaires during AICT, showed no correlation with the high-order measures. The proposed study is the first exploratory attempt to utilize the concepts of synergy and redundancy in NSCs. The differences in synergy and redundancy during different NSCs warrant further studies to relate the extracted measures with the phenomenology of the NSCs.

Cedrol supplementation ameliorates memory deficits by regulating neuro-inflammation and cholinergic function in lipopolysaccharide–induced cognitive impairment in rats

BackgroundCedrol, a sesquiterpene alcohol, is found in a high amount in several conifers. It possess several beneficial health effects, including antioxidant and anti-inflammatory properties. Objective: This study evaluates the neuroprotective role of cedrol against lipopolysaccharide (LPS)-induced neuroinflammation and memory loss in rats. MethodsWistar rats were treated with cedrol (7.5, 15, and 30 mg/kg, oral, two weeks). During the last week, the rats (except for the control group) were treated with LPS (intraperitoneal injection, 1 mg/kg) to induce memory impairment. After that, the animals were subjected to behavioral studies (Morris water maze and passive avoidance) and biochemical assessments. ResultsOur results showed a significant decrease in learning and memory function-in LPS-induced rats which were reversed by cedrol. Also, there was a significant increase in the cerebral levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and malondialdehyde (MDA) as well as acetylcholinesterase (AChE) activity in LPS-treated rats. Besides, a significant reduction in total thiol and superoxide dismutase levels was observed in LPS-treated rats. However, cedrol significantly decreased the brain level of AChE, TNF-α, and IL-1β. Administration of cedrol also restored the oxidative stress markers. Conclusionthe beneficial effects of cedrol against LPS-induced memory impairment could be due to antioxidant activities and modulation of neuro-inflammatory mediators.

Proteolytic system parameters in the brain of rats with hyperhomocysteinemia

Hyperhomocysteinemia (HHcy) is now being actively studied as a potential risk factor and/or biomarker for numerous pathological conditions, including brain diseases. This study aimed to analyze the proteolytic processes in the brains of rats with HHcy. Total proteolytic activity, metal-dependent, and serine proteases activities, the content of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases-1, cytokines, serine proteases, total protein and medium and low molecular-weight substances (MLMWS), were evaluated. HHcy was induced by DL-homocysteine thiolactone (HTL) daily intragastric administration (200 mg·kg–1 of body weight) to young and adult albino non-linear male rats for 8 weeks following rat sacrifice and brain harvesting. It was established that HHcy causes an increase in total proteolytic activity and a rise in MLMWS levels in rat brains. Serine protease activity increased to a greater extent compared to metal-dependent one, and bigger changes were observed in young rats. Rise in MMP-9 and -10 levels (in young animals), a decline in MMP-3 and -8 levels, and a decrease in the content of interleukin-1β, interferon-γ, interleukin-4 and tumor necrosis factor-α (the last two in young animals) was also detected. No significant changes were found in serine protease content. Therefore, proteolysis intensification in the brain of rats with HHcy is more likely caused by protease up-regulation through mechanisms stimulated by homocysteine, HTL, and oxidative stress, without involving pro-inflammatory signaling pathways.

The gut microbiome promotes locomotion of Drosophila larvae via octopamine signaling.

The gut microbiome is a key partner of animals, influencing various aspects of their physiology and behaviors. Among the diverse behaviors regulated by the gut microbiome, locomotion is vital for survival and reproduction, although the underlying mechanisms remain unclear. Here, we reveal that the gut microbiome modulates the locomotor behavior of Drosophila larvae via a specific neuronal type in the brain. The crawling speed of germ-free (GF) larvae was significantly reduced compared to the conventionally reared larvae, while feeding and excretion behaviors were unaffected. Recolonization with Acetobacter and Lactobacillus can fully and partially rescue the locomotor defects in GF larvae, respectively, probably due to the highest abundance of Acetobacter as a symbiotic bacterium in the larval gut, followed by Lactobacillus. Moreover, the gut microbiome promoted larval locomotion, not by nutrition, but rather by enhancing the brain levels of tyrosine decarboxylase 2 (Tdc2), which is an enzyme that synthesizes octopamine (OA). Overexpression of Tdc2 rescued locomotion ability in GF larvae. These findings together demonstrate that the gut microbiome specifically modulates larval locomotor behavior through the OA signaling pathway, revealing a new mechanism underlying larval locomotion regulated by the gut microbiome.

The 5HT2b Receptor in Alzheimer's Disease: Increased Levels in Patient Brains and Antagonist Attenuation of Amyloid and Tau Induced Dysfunction.

Background: Neurodegenerative diseases manifest behavioral dysfunction with disease progression. Intervention with neuropsychiatric drugs is part of most multi-drug treatment paradigms. However, only a fraction of patients responds to the treatments and those responding must deal with drug-drug interactions and tolerance issues generally attributed to off-target activities. Recent efforts have focused on the identification of underexplored targets and exploration of improved outcomes by treatment with selective molecular probes. As part of ongoing efforts to identify and validate additional targets amenable to therapeutic intervention, we examined levels of the serotonin 5-HT2b receptor (5-HT2bR) in Alzheimer's disease (AD) brains and the potential of a selective 5-HT2bR antagonist to counteract synaptic plasticity and memory damage induced by AD-related proteins, amyloid-β, and tau. This work used a combination of biochemical, chemical biology, electrophysiological, and behavioral techniques. Biochemical methods included analysis of protein levels. Chemical biology methods included the use of an in vivo molecular probe MW071, a selective antagonist for the 5HT2bR. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated spatial memory and associative memory. 5HT2bR levels are increased in brain specimens of AD patients compared to controls. 5HT2bR antagonist treatment rescued amyloid-β and tau oligomer-induced impairment of synaptic plasticity and memory. The increased levels of 5HT-2bR in AD patient brains and the attenuation of disease-related synaptic and behavioral dysfunctions by MW071 treatment suggest that the 5HT-2bR is a molecular target worth pursuing as a potential therapeutic target.